TY - JOUR
T1 - Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit
AU - Gazit, Aviv
AU - Yee, Kevin
AU - Uecker, Andrea
AU - Böhmer, Frank D.
AU - Sjöblom, Tobias
AU - Östman, Arne
AU - Waltenberger, Johannes
AU - Golomb, Gershon
AU - Banai, Shmuel
AU - Heinrich, Michael C.
AU - Levitzki, Alexander
N1 - Funding Information:
Supported in part by a Infrastructure grant from the Ministry of Science in Jerusalem, Israel to A.L., in part from the Minfunding, from a VA Merit Review Grant (M.C.H.) and the Doris Duke Charitable Foundation (M.C.H. and K.Y) and in part by the Deutsche Forschungsgemeinschaft: Wa734/4-2 and the Heisenberg Scholarship to J.W.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is ∼15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
AB - Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is ∼15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
UR - http://www.scopus.com/inward/record.url?scp=0037401818&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(03)00048-8
DO - 10.1016/S0968-0896(03)00048-8
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C2 - 12670652
AN - SCOPUS:0037401818
SN - 0968-0896
VL - 11
SP - 2007
EP - 2018
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 9
ER -